The present invention relates generally to body implantable stents, deployed in a vessel, tract, channel or duct, such as a coronary artery or femoral artery of a patient to maintain its lumen open for satisfactory blood flow therethrough, and more particularly to methods of producing multi-layer stent structures in which an oxide of a noble metal or alloy is bonded in a firm and stable relationship to an underlying non-noble or less-noble metal, and to such stent structures themselves.
When inserted and deployed in a vessel, duct, channel or tract (referred to generally herein, for convenience, as a vessel) of the body—for example, a coronary artery after dilatation of the artery by balloon angioplasty—a stent acts as a scaffold to maintain the vessel's lumen open. The stent prosthesis is structured as an open-ended tubular element with through-holes in its sidewall to allow expansion of its diameter from a first sufficiently small size to permit navigation of the stent, mounted on a balloon catheter, through the vessel to the target site where it is to be deployed, to a second fully deployed sufficiently large size to engage the inner lining of the vessel's wall for retention at the target site.
A coronary artery, for example, may become occluded from a buildup of fatty deposits or plaque on the inner lining of the vessel's wall. The artery blockage may be detected through an electrocardiogram performed during the individual's visit to a doctor, or be so extreme as to result in angina or even myocardial infarction. Typically, the procedure performed to relieve the blockage is balloon angioplasty, in which a balloon catheter is inserted into the vessel until the balloon is at the target site as monitored under fluoroscopy, the balloon is inflated to compress the fatty deposits against the inner lining of the vessel wall to open the lumen, and the catheter is then withdrawn from the patient. Other procedures may alternatively be performed for relieving the blockage, but for a relatively large percentage of angioplasty patients a new blockage of the treated vessel typically occurs only a few months later. The new blockage is usually attributable to trauma to the vessel wall that arises from the original angioplasty procedure, but the mechanism responsible for this restenosis or re-occlusion of the vessel lumen is intimal hyperplasia, a rapid proliferation of smooth muscle cells along the treated region of the vessel wall, quite different from the causation of the original blockage.
As noted above, it is customary to install a stent at the trauma site to maintain the vessel lumen open, often in a procedure accompanying or shortly after the angioplasty procedure. The stent is mounted in a crimped state on the balloon of a balloon catheter for advancement through the appropriate portion of the patient's cardiovascular system to the target site, also under x-ray fluoroscopy, where the balloon is inflated to deploy the stent by expansion of the stent diameter under the outwardly directed radial pressure exerted by the balloon. The outer surface of the stent is thereby forced into engagement with and exerts pressure on the inner lining of the vessel wall. The stent structure has sufficient resilience to allow some contraction of the diameter of the stent under the force exerted on it by the natural recoil of the vessel wall, but has sufficient stiffness to largely withstand the recoil and hold open the lumen of the vessel at the implant site.
The presence of the stent in contact with the vessel wall, however, can promote hyperplasia and resulting restenosis, and, along the stent's inner surface, may promote thrombus formation with the perfusion of blood through the stent's lumen. To avoid acute blockage of the vessel lumen owing to these reactions in some patients, drug coated stents are being prescribed on an almost regular basis. The outer surface of the stent to be implanted may be coated with an antiproliferative or immunosuppressive agent, while the inner surface may be coated with an antithrombotic agent. Drug coated stents are considerably more expensive than uncoated stents, and may be unnecessary for a relatively large percentage of angioplasty patients in which they are implanted, being prescribed solely to avoid the possibility of an undesirable reaction soon thereafter.
On the other hand, the use of uncoated stents has its own set of problems even beyond possibly inducing a traumatic response along the vessel wall or promoting thrombosis along the stent's lumen. The material of which the stent is composed can induce an allergic reaction in a statistically significant percentage of the patient population. These include commonly used stent materials such as chrome, nickel, and even medical grade 316L stainless steel—which contains about 16% nickel. Stent implants are contraindicated in many such allergic patients. Wholly biodegradable stents of possibly sufficient radial strength are undergoing testing but appear unlikely to constitute a breakthrough or a satisfactory solution in these cases.
Another consideration in material selection is the need for the implanting physician to be able to see the advancement and positioning of the stent as it is being implanted at the specified target site in the body, typically by x-ray fluoroscopy. The thickness of a metallic stent wall is made sufficient to withstand the aforementioned vessel wall recoil that invariably follows stent deployment and to hold the vessel lumen open. But it is also necessary that the calculation of stent wall thickness take into account the dimension necessary to render the stent visible with fluoroscopy, given the type of material of which the stent is composed. Various materials, such as 316L stainless steel, possess suitable mechanical strength to maintain an open vessel lumen, with smaller wall thickness than is required to provide fluoroscopic visibility. Typical conventional stent wall or wire thicknesses have ranged up to about 200 microns (or micrometers, μm). A 70 to 80 μm thick 316L steel stent, for example, offers sufficient mechanical strength for the aforementioned purposes, but is too thin to create the shadow needed for fluoroscopic viewing because the x-ray absorption of this metal is so low. Increasing the wall thickness of the stent to enhance its radiopacity makes the stent less flexible, which adversely affects its maneuverability through narrow vessels during implantation, and its ease of expansion during deployment, with concomitant increased risk of balloon rupture.
It follows that for successful interventional use, the stent should possess characteristics of relatively non-allergenic reaction, good radiopacity, freedom from distortion on magnetic resonance imaging (MRI), flexibility with suitable elasticity to be plastically deformable, resistance to vessel recoil, sufficient thinness to minimize obstruction to flow of blood (or other fluid or material in vessels that require stenting other than the cardiovascular system), and biocompatibility to avoid vessel re-occlusion. Stent material, as well as stent design, plays a role in achieving these characteristics.
Aside from vascular usage, other vessels of the human body in which a stent might be installed to maintain an open lumen include the tracheo-bronchial system, the biliary hepatic system, the esophageal bowel system, and the urinary tract, to name a few. Many of the same requirements are found in these other endoluminal usages of stents.
Despite improvements in the design, construction and coating of coronary stents, restenosis remains a problem. A major contributing factor is the inability of the body to quickly incorporate the implanted foreign material of the stent. Basic research with cell cultures, as well as animal experiments, demonstrate that the degree of endothelialization of the foreign body is a determinant of the amount of the restenosis caused by the presence of that body. It had been assumed by industry practitioners and researchers that a highly polished and smooth surface is beneficial to prevent stent thrombosis and to facilitate endothelialization, but more recent experiments indicate this may not be entirely true.
A main reason for the lack of sufficient clinical success rate with electropolished stents is that the smooth muscle cells that seek to envelop a foreign body must undergo greater proliferation to cover the polished stent. The continuing flow of blood with high pressure and high shearing stress prevents the migration of smooth muscle cells that proliferate from the media and adventitial cells of a stented vessel such as a coronary artery. Indeed, a slightly rough surface appears to facilitate considerably more coverage by smooth muscle cells, which leads to a functional endothelial layer some 10 to 14 days after stent implantation. A single layer of endothelial cells has been found to seal the neointima, and thereby to prevent the stimulus that facilitates proliferation of cells beyond mere coverage of the foreign body.
As is intuitively obvious, the thinner the stent strut, the less wall thickness of the stent invades the lumen of the stented vessel. And a thin stent is more easily covered by a neoendothelial build-up. Accordingly, it is desirable to make the stent wall as thin as possible. But, again, fluoroscopic visibility of the structure has a role in determining its thickness for a given material.
Some improvement in visibility is achieved by application of an adherent, more radiopaque layer to the surface of a stent core material of medical grade implantable 316L stainless steel. These radiopaque layer materials include gold and certain other noble metals, such as platinum. Their considerably greater radiopacity relative to stainless steel renders the stent highly visible under fluoroscopy. The materials are also substantially non-allergenic and non-thrombogenic. The coating may be applied in a very thin layer, leaving the determinant of stent wall thickness almost solely the requirement of mechanical strength. The coating must be capable of absolute adherence to the underlying metal of the stent to avoid cracking or defects in the homogeneous overlying layer, and sufficient resistance to peeling or flaking of the coating material both during insertion of the stent, expansion of the diameter of the stent as it is being deployed in final position, and throughout the entire time the stent remains in that position—objectives which are not easily achievable. The presence of cracks or related defects in the surface coating can produce a galvanic potential that could ultimately lead to corrosion of the underlying steel or lesser metal, an unacceptable situation for a device intended to be permanently implanted in the body. Therefore, manufacturing requires a high degree of quality control and concomitant high cost.
U.S. Pat. No. 6,099,561, of the same assignee, discloses a stent structure with three fundamental layers, a first underlying substrate of a stent metal that functions to provide high mechanical strength, a second intermediate layer that functions to provide high fluoroscopic visibility—such as a noble metal layer or alloy thereof—, and a top layer of a particularly beneficial biocompatible material—designated to be a ceramic-like material such as iridium oxide or titanium nitride. The intermediate layer of elemental noble metal or an alloy thereof is uninterrupted by gaps or pockets along its length, and is highly adherent for tight coverage and substantially uniform thickness. This intermediate layer tends to avoid the creation of a galvanic potential that would lead to corrosion of the lesser, underlying metal. Such a condition might otherwise exist if, without the presence of an intermediate uninterrupted noble metal layer, a layer of ceramic-like metal were to overlie and adhere to the base metal at points where fissures could exist. The multi-layer stent of the '561 patent exhibits mechanical strength, small physical dimensions, increased visibility, long-term stability, and a highly biocompatible surface that enables rapid endothelialization with low occurrence of restenosis. But it is expensive to produce.
U.S. Pat. No. 6,387,121, of the same assignee as the present application, discloses a multi-layer stent with a thin, continuous intermediate layer of metal or alloy of niobium, zirconium, titanium or tantalum overlying the surface of the stent's tubular metal base, and an outer layer of iridium oxide overlying the intermediate layer with interstices for storing and dispensing (eluting) drugs.
U.S. Pat. No. 6,478,815, also assigned to the same assignee as this application, discloses a stent composed of niobium with a trace of another metal, such as zirconium, titanium or tantalum for alloy formation and reinforcement. Also, a surface coating of iridium oxide or titanium nitrate may be applied to the niobium structure to aid in inhibiting vessel closure, as with the previous patent disclosures mentioned herein. This stent is beneficial, enjoying many of the advantages that have been sought as discussed above, with only two layers in the stent structure.
A stability problem may be encountered in the bond between the noble metal oxide layer, such as iridium oxide, and a non-noble or less-noble metal, alloy or compound, such as niobium or platinum enriched medical grade stainless steel. During the bonding process the less noble metal tends to draw or leach oxygen atoms from the noble metal, which causes depletion of oxygen from the latter metal. The result can be a less stable, less satisfactory bond or adhesion between the two layers. In addition, in the case of an iridium oxide layer as the noble metal oxide, the oxygen depletion leaves that layer less effective as a stenosis or restenosis inhibitor.